The present invention is novel compounds which are 3,5-di-tertiary-butyl-4-hydroxyphenyl substituted 1,2,4- and 1,3,4-thiadazoles and oxadiazoles, and 1,2,4-triazoles, and pharmaceutically acceptable acid addition or base salts thereof, pharmaceutical compositions and methods of use therefor. The invention compounds are now found to have activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, pyrrhia, and the like. Thus, the present invention is also a pharmaceutical composition or method of use therefor.
U.S. Pat. No. 4,618,617 includes a generic disclosure for 1,2,4-oxadiazole derivatives of groups which may be read to include 3,5-di-tertiary butyl-4-hydroxy phenyl substituents. However, none of the disclosure specifically shows the unexpected activity of combined ring systems of the present oxadiazole and 3,5-ditertiary-butyl-4-hydroxyphenyl groups. Similarly, J61005-072-A of Derwent Abstract No. 86-051943/08 does not recognize the advantages of the present ring combination.
3,5-di-tertiary-butyl-4-hydroxyphenyl substituents are also shown on pyrrole ring-containing compounds in European Application No. 269,981 abstracted as Derwent Abstract No. 88-15622/423, showing usefulness as analgesic, antipyretic, antiinflammatory, and antipsoriatic agents, and for treating bone disorders.
A 3,5-di-tertiarybutyl-4-substituted benzylidene on a ##STR1## ring is disclosed for use as antiinflammatory, analgesic, antipyretic, and antiplatelet aggregation agents in an abstract of Japanese Application 88024498 in the Derwent Alerting Bulletin J8-B, Vol. 88, No. 21 by Kanegafuchi Kagaku.
A 3,5-di-tertiarybutyl-4-hydroxybenzyl substituent for 2-pyrrolidone derivatives as antiinflammatory, analgesic, and antipyretic agents is taught by Japanese Application No. J63119-461 and J63115-859 in Derwent Abstract No. 88-180570/26 and 88-178973/26, respectively, by Eisai KK.
Other compounds disclosing either specifically or generically 3,5-di-tertiarybutyl-4-hydroxy substituents include compounds that are, for example, 3-ethenylpyridines, in U.S. Pat. No. 4,743,606 abstracted in Derwent Abstract No. 88-147234/21 and ##STR2## wherein L is lower alkylene, sulphur or sulphinyl; and Y is alkoxyimino, or oxo; A-B- is CH--CH.sub.2 -- or
C.dbd.CH--; and Z is lower alkylene or sulphur; in Japanese Application No. J62,081,343 in Derwent Abstract 87-140934/20.
Also, thiazolidinone derivatives are shown in European Application No. 211670 by Eli Lilly and Co. of Derwent Abstract No. 87-051809/08 and thiazole derivatives in Japanese Application No. 62132871 by Yamanouchi Pharm KK discussed in Derwent Abstract No. 87-203585/29. In the Lilly disclosure the ring systems were linked by a saturated carbon group.
Thus, the differences between the present invention and the teachings of the references are readily apparent.